Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice

Int J Cancer. 2004 Jul 1;110(4):481-90. doi: 10.1002/ijc.20175.

Abstract

We recently showed that zerumbone, a sesquiterpene found in subtropical ginger, suppresses colonic tumor marker formation in rats and induces apoptosis in colon cancer cell lines. In our present study, the anti-tumor initiating and promoting activities of zerumbone in mouse skin were evaluated using a conventional 2-stage carcinogenesis model. A single topical pretreatment to mouse skin (2 micromol) 24 hr before application of dimethylbenz[a]anthracene (0.2 micromol) markedly suppressed tumor incidence by 60% and the number of tumors by 80% per mouse. Repeated pretreatment (16 nmol) twice weekly during the post-initiation phase reduced the number of 12-O-tetradecanoylphorbol-13-acetate (TPA, 1.6 nmol)-induced tumors by 83% as well as their diameter by 57%. Multiple reverse transcriptase (RT) PCR experiments revealed that zerumbone (2 micromol) enhanced the mRNA expression level of manganese superoxide dismutase, glutathione peroxidase-1, glutathione S-transferase-P1 and NAD(P)H quinone oxidoreductase in the epidermis, but not that of cytochrome p450 1A1 or 1B1. Further, it diminished TPA-induced cyclooxygenase-2 protein expression and phosphorylation of extracellular signal-regulated kinase 1/2, while pretreatment(s), in either the priming or activation stage or both, reduced double TPA application-induced hydrogen peroxide formation and edema induction by 29% to 86%, respectively. Histologic examination revealed that pretreatment(s) with zerumbone suppressed leukocyte infiltration and reduced proliferating cell nuclear antigen-labeling indices. Together, our results indicate that zerumbone is a promising agent for the prevention of both tumor initiating and promoting processes, through induction of anti-oxidative and phase II drug metabolizing enzymes as well as attenuation of proinflammatory signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology*
  • Cyclooxygenase 2
  • Enzyme Induction / drug effects
  • Female
  • Glutathione S-Transferase pi
  • Glutathione Transferase / genetics
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Mice
  • Mice, Inbred ICR
  • Mitogen-Activated Protein Kinases / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • Oxidative Stress / drug effects
  • Phosphorylation
  • Prostaglandin-Endoperoxide Synthases
  • Sesquiterpenes / pharmacology*
  • Skin Neoplasms / prevention & control*
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Anticarcinogenic Agents
  • Isoenzymes
  • Sesquiterpenes
  • zerumbone
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Glutathione S-Transferase pi
  • Glutathione Transferase
  • Gstp1 protein, mouse
  • Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate